108
et al. 2017; Aroso et al. 2016; Dai et al. 2013; Francisco et al. 2013). Different theories were reported to explain the formation of eutectic mixtures as stable liquids,
namely, the idea of a cluster formation or a mechanical mixture of the components.
Abbott and coworkers suggested hydrogen bond interactions, in which the mixture
results from the interactions between a hydrogen bond donor and a hydrogen bond
acceptor, which leads to lowering the entropic differences of the phase transitions
and allows decreasing the melting point (Francisco et al. 2013; Pedro et al. 2019).
The nature of the interactions between the components could affect the capacity of
the initial compounds to interact, and the charge delocalization could modulate the
different physicochemical properties of DES, when compared to initial components, since the interactions could be hydrogen bonds, van der Waals, and/or electrostatic forces (Francisco et al. 2013; Santana et al. 2019). The van der Waals
interactions in liquids could be observed by molecular dynamics using the empirical
Lennard-Jones (LJ) equation that includes repulsive and attractive forces
(Wojnarowska et al. 2018). The higher capacity of the components to establish
hydrogen bonds is related with the phase-transition temperature and stability of the
components (Francisco et al. 2013).
DES represent a group of systems that can be prepared from a variety of compounds, which may lead to thousands of different combinations (up to 10
6
) (Barros
et al. 2017; Francisco et al. 2013). These systems emerged as alternative candidates
to ionic liquids and have also been described as low transition temperature mixtures
(LTTM) (Durand et al. 2016). In 2011, Choi and coworkers reported 30 different
combinations with choline chloride, natural carboxylic acids, sugars, and water that
form viscous liquids and were named as natural deep eutectic solvents (NADES).
NADES could be eutectic mixtures that we observe in our daily life; as an example,
honey and syrup are eutectic mixtures of sugars at room temperature, and they could
be used in food, as dietary supplement, and for medical formulations, because they
are easily biodegradable and often have low toxicity (Fig. 3.2) (Choi et al. 2011; Dai
et al. 2015; Liu et al. 2018a, b; Kudlak et al. 2015).
The use of eutectic mixtures for therapeutic applications was reported decades
ago for transdermal delivery of anesthetic and anti-inflammatory drugs (Evers et al.
1985). Later, Stott and coworkers observed that ibuprofen could form eutectic mixtures with different terpenes and enhance skin permeation, dissolving API and
increasing its solubility, permeability, and absorption (Aroso et al. 2015; Stott et al.
1998). In 2015, Aroso and coworkers named these solvents as therapeutic deep
eutectic systems (THEDES), and they include deep eutectic systems that have an
API incorporated in the mixture or a DES that can dissolve an API and improve
their characteristics in terms of bioavailability and toxicity (Aroso et al. 2015; Gala
et al. 2014; Wojnarowska et al. 2018) (Fig. 3.3).
3.2.1 Eutectics in Pharmacy
The term eutectic is derived from the Greek word eutectos, which means easily
fused, and it was used for the first time by Frederik Guthrie, in 1884, to describe
“bodies made up of two or more constituents, which constituents are in such
F. Santos and A. R. C. Duarte
et al. 2017; Aroso et al. 2016; Dai et al. 2013; Francisco et al. 2013). Different theories were reported to explain the formation of eutectic mixtures as stable liquids,
namely, the idea of a cluster formation or a mechanical mixture of the components.
Abbott and coworkers suggested hydrogen bond interactions, in which the mixture
results from the interactions between a hydrogen bond donor and a hydrogen bond
acceptor, which leads to lowering the entropic differences of the phase transitions
and allows decreasing the melting point (Francisco et al. 2013; Pedro et al. 2019).
The nature of the interactions between the components could affect the capacity of
the initial compounds to interact, and the charge delocalization could modulate the
different physicochemical properties of DES, when compared to initial components, since the interactions could be hydrogen bonds, van der Waals, and/or electrostatic forces (Francisco et al. 2013; Santana et al. 2019). The van der Waals
interactions in liquids could be observed by molecular dynamics using the empirical
Lennard-Jones (LJ) equation that includes repulsive and attractive forces
(Wojnarowska et al. 2018). The higher capacity of the components to establish
hydrogen bonds is related with the phase-transition temperature and stability of the
components (Francisco et al. 2013).
DES represent a group of systems that can be prepared from a variety of compounds, which may lead to thousands of different combinations (up to 10
6
) (Barros
et al. 2017; Francisco et al. 2013). These systems emerged as alternative candidates
to ionic liquids and have also been described as low transition temperature mixtures
(LTTM) (Durand et al. 2016). In 2011, Choi and coworkers reported 30 different
combinations with choline chloride, natural carboxylic acids, sugars, and water that
form viscous liquids and were named as natural deep eutectic solvents (NADES).
NADES could be eutectic mixtures that we observe in our daily life; as an example,
honey and syrup are eutectic mixtures of sugars at room temperature, and they could
be used in food, as dietary supplement, and for medical formulations, because they
are easily biodegradable and often have low toxicity (Fig. 3.2) (Choi et al. 2011; Dai
et al. 2015; Liu et al. 2018a, b; Kudlak et al. 2015).
The use of eutectic mixtures for therapeutic applications was reported decades
ago for transdermal delivery of anesthetic and anti-inflammatory drugs (Evers et al.
1985). Later, Stott and coworkers observed that ibuprofen could form eutectic mixtures with different terpenes and enhance skin permeation, dissolving API and
increasing its solubility, permeability, and absorption (Aroso et al. 2015; Stott et al.
1998). In 2015, Aroso and coworkers named these solvents as therapeutic deep
eutectic systems (THEDES), and they include deep eutectic systems that have an
API incorporated in the mixture or a DES that can dissolve an API and improve
their characteristics in terms of bioavailability and toxicity (Aroso et al. 2015; Gala
et al. 2014; Wojnarowska et al. 2018) (Fig. 3.3).
3.2.1 Eutectics in Pharmacy
The term eutectic is derived from the Greek word eutectos, which means easily
fused, and it was used for the first time by Frederik Guthrie, in 1884, to describe
“bodies made up of two or more constituents, which constituents are in such
F. Santos and A. R. C. Duarte